Our research has identified that changes in the ocular surface environment of dry eye, such as a hyperosmolar tear film, stimulate the production of pro-inflammatory cytokines by the ocular surface epithelia. Our preliminary data suggests that these cytokines, particularly interleukin-1 (IL-1) and TNF-alpha, may play a key role in the pathogenesis of the epithelial and immuno-pathology of keratoconjunctivitis sicca, (KCS) the ocular surface disease of dry eye. Four proposed Specific Aims will test this theory. Aim I will confirm whether experimentally induced dry eye in mice stimulates the production and release of pro-inflammatory cytokines by the ocular surface epithelium that promote ocular surface inflammation and KCS. Aim 2 will determine whether hyperosmolar stress stimulates the production of pro-inflammatory cytokines by the ocular surface epithelium by activating the p38 stress activated protein kinase pathway. Aim 3 will study the expression of IL-1 and TNF-alpha receptors on the ocular surface and determine if there are differences in the expression of these receptors and their soluble antagonists between normal and dry eyes. Aim 4 will investigate the effects of the pro-inflammatory cytokines of dry eye on the expression of matrix metalloproteinase enzymes (MMPs) and mucins on the ocular surface. These factors that have been implicated in the disruption of ocular surface barrier function and homeostasis in KCS. These studies will provide clinically relevant information regarding the role of inflammation and its cytokine mediators on the pathogenesis of the ocular surface disease of dry eye, a condition experienced by over 10 percent of the population over the age of 30.